Topical ophthalmic analgesic preparations for sustained and extended corneal analgesia

ABSTRACT

A preparation suitable for sustained and extended corneal analgesia and for repeated administration consisting of ultralow nontoxic subanaesthetic concentrations of local anesthetic agents. A method for corneal analgesia has a fast onset of pain relief and extended duration of the corneal analgesia for several months without accompanying toxic symptoms by administering to a patient an ophthalmic analgesic solution containing a local anesthetic agent in subanesthetic concentration.

This is a continuation-in-part application of application Ser. No.08/415,184 filed on Apr. 3, 1995, issued as U.S. Pat. No. 5,610,184 onMar. 11, 1997 which is a continuation-in-part application of theapplication Ser. No. 08/183,186 filed on January 14, 1994 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of Invention

The current invention concerns a topical ophthalmic analgesicpreparations containing ultralow nontoxic subanaesthetic concentrationsof local anesthetic agents for sustained and extended corneal analgesiaby repeated administration. In particular, the invention concerns atopical ophthalmic preparation for corneal analgesia having a fast onsetof pain relief and extended duration of the corneal analgesia. Thepreparation may be administered for several months without accompanyingtoxic symptoms. The topical analgesic preparation contains a localanesthetic agent in ultralow subanaesthetic concentration. The analgesicmicrodose system contains concentration between about 0.001 and 1.0% ofthe anesthetic agent per 1-10 μl.

2. Background Art and Related Art Disclosers

Trauma to the eye, particularly corneal injury and abrasion, tends to beexcruciatingly painful. While many anesthetic agents such asproparacaine, cocaine, procaine, tetracaine, hexylcaine, bupivacaine,lidocaine, benoxinate, mepivacaine, prilocaine and etidocaine, to name afew, are well known to attain temporary anesthesia and suppression ofpain, concentrations of these agents needed to achieve cornealanesthesia are between 0.25% and 4%. At these concentrations, theseagents can only be administered for a very short period of timenecessary to achieve local anesthesia and permit performance ofophthalmic procedures such as examination of a painful eye, measurementof intraocular pressure, gonioscopic examination, removal of foreignbodies and sutures from the cornea, diagnostic conjunctival and cornealscrapings, radial keratotomy, and other surgical procedures. The onsetof the anesthesia is very rapid, typically under 15 seconds, andtypically lasts for about 10-30 minutes. Unfortunately, application oflocal anesthetics to the cornea at these concentrations causes thedevelopment of temporary superficial corneal epithelial lesions. Uponrepeated application for prolonged anesthesia, these lesions progress toextensive erosions of the corneal epithelium and grayish infiltrates ofthe corneal stroma which can lead to permanent scarring and loss ofvision. Prolonged application of local anesthetics is further associatedwith delayed corneal reepithelialization after wounding, alteredlacrimation and tear film stability, corneal swelling, and disruption ofepithelial cell mitosis and migration.

It is therefore clear that the use of local anesthetics in their normaland intended manner is limited to short-term anesthesia and cannot besafely utilized for sustained decrease or elimination of pain overseveral hours or days.

Anesthesia, which is a partial or total loss of the sense of pain,temperature, and touch, is very different from analgesia, a state inwhich the individual does not feel pain but feels other sensations, suchas touch or temperature.

Sustained ophthalmic analgesia is very difficult to achieve. This isparticularly true with respect to corneal analgesia. The cornea is theclear dome-shaped window in the front of the eye. The cornea serves twofunctions. First, it forms the front part of the eye's outer wall andthus protects structures inside the eye. Second, with its curved shape,the cornea acts like a camera lens to transmit light and focus images onthe retina at the back of the eye. The epithelium (outermost layer) ofthe cornea is heavily innervated. Therefore, the cornea is verysensitive, and any damage to the surface epithelium can cause severepain.

A common cause of such pain is a break in the corneal epithelium. Suchepithelial defects can be caused by corneal drying, infection andinflammation which damage epithelial cells, by corneal dystrophies withloosely adherent epithelium, or by mechanical removal of the cornealepithelium in traumatic abrasions or surgical procedures. In most cases,the pain persists until the epithelial defect has healed.

At present, in order to provide immediate but short-term alleviation ofthe severe pain experienced by patients suffering from cornealepithelial defects, commercially available local anesthetics can beapplied topically to the eye, providing rapid onset of short-actingcorneal anesthesia. Two commonly used topical anesthetics areproparacaine in a concentration of 0.5% (5,000 μg/ml) and tetracaine0.5% (5,000 μg/ml). Lidocaine 4% (40,000 μg/ml) is also occasionallyused.

While short-term relief from pain accompanies the application of theseanesthetics, there are conditions of the cornea where such short termrelief from pain is not sufficient and where prolonged analgesia isnecessary and desirable. This is especially true for relief of painassociated with corneal epithelial defects. In these instances, thetoxicity associated with repeated use of topical anesthetics forachieving sustained corneal analgesia has been well documented. InOcular Pharmacology, Fifth Edition, C. V. Mosby, St. Louis, pages 75-76(1983), the repeated use of anesthetic concentrations of topicalanesthetics was found to be detrimental to the cornea, and the articlestates that the repeated use of anesthetics is prohibited because oftheir toxicity. Thus, the toxicity of these anesthetic agents precludestheir repeated use for prolonged corneal analgesia. At this time,therefore, acceptable methods for long-term relief of corneal pain arelimited to patching and oral analgesics.

Patching provides partial pain relief in some patients by reducingeyelid movement over the corneal surface and limiting exposure to theoutside environment. However, patching has many disadvantages. It isdifficult for the patient to reapply the patch properly when it becomesloose or soiled. Patching restricts the frequent use of topicalmedications. It raises the temperature of the eye surface and thussupports the growth of microorganisms. Finally, many patients areuncomfortable with an eye patched. While patching with a bandage softcontact lens may overcome some of these problems, patching providesincomplete pain relief in most patients and is no substitute forsustained analgesia in patients suffering from corneal epithelialdefects, where the pain can persist for several days to several weeks ormonths.

Oral agents are reasonably effective in reducing corneal pain. However,onset of action is gradual and slow rather than immediate. Dosesadequate for corneal analgesia are high and usually cause significantgeneralized sedation, occasionally accompanied by nausea and vomitingand rarely by life-threatening allergic reactions.

It would therefore be highly desirable and advantageous to haveavailable a method for treatment of acute and chronic corneal painwithout exposing a patient to the undesirable side effects of currentlyavailable oral analgesics, to the inadequate analgesia and inconvenienceassociated with patching, or to the toxic effects of repeated doses ofcurrently available concentrations of topical anesthetics.

It is therefore the primary object of this invention to provide a methodfor achieving sustained and extended corneal analgesia by administrationof ultralow concentrations of local anesthetic agents formulated intopical ophthalmic analgesic solutions or ophthalmic analgesicpreparations.

SUMMARY

One aspect of the current invention is a topical ophthalmic preparationfor sustained corneal analgesia for topical administration ofsubanaesthetic concentrations of local anesthetics.

Another aspect of the current invention is a topical ophthalmicpreparation for relief of corneal pain formulated as an ointment, cream,suspension, solution, gel or a sustained release vehicle containing anultralow concentration of from 0.0001% to about 0.05% of localanesthetic sufficient to assert an analgesic effect but not causeophthalmic anesthesia.

Still another aspect of the current invention is a topical ophthalmicpreparation for alleviating corneal pain by administration of anophthalmic analgesic solution or preparation containing a localanesthetic in concentrations from about 0.001% to about 0.05%.

Still another aspect of the current invention is a topical ophthalmicpreparation for alleviating corneal pain administered in a microdoseusing a microsystem wherein a local anesthetic is present inconcentrations from about 0.001% to about 1.0% per 1-10 μl dose.

Still yet another aspect of the current invention is a method for safelyalleviating corneal pain by administration of an ophthalmic analgesicsolution or preparation containing an ultralow concentration of localanesthetic on an as needed basis decided by the patient, as often andfor as long as necessary.

Still yet another aspect of the current invention is a topicalophthalmic analgesic preparation consisting essentially of about0.001%-0.05% local anesthetic selected from the group consisting ofproparacaine, tetracaine and lidocaine formulated as an ointment, gel,cream, suspension or a sustained release vehicle containingpharmaceutically acceptable excipients, additives and preservatives.

DEFINITIONS

As used herein:

"Local anesthetics" means any anesthetics which can be administeredlocally. Examples of such anesthetics are proparacaine, lidocaine,tetracaine, procaine, cocaine, hexylcaine, bupivacaine, benoxinate,mepivacaine, prilocaine, chloroprocaine, propoxycaine, dyclonine,pramoxine, benzocaine, dibucaine, and etidocaine.

"Ultralow concentration" means a concentration from about 0.001% toabout 0.05%, that is, from about 10 μg to about 500 μg per one dose ofophthalmic preparation.

"Dose" means a measurable amount of the ophthalmic analgesic for properdosage containing from about 0.001% to about 0.05% of the localanesthetics.

"Microsystem" means a microdose or microdrop system wherein a topicalanesthetic is present in concentrated form which is diluted by naturaltearing process to subanaesthetic concentrations not causing anesthesia.

"Microdose" or "microdrop" means a measurable amount of the ophthalmicanalgesic present in one dose or one drop of a microsystem containingsubanaesthetic concentration from about 0.001% to about 1.0% of thelocal anesthetics diluted and administered in 1-10 μl of aqueoussolution.

"Ophthalmic analgesic preparation" means any cream, gel, solution,sustained release vehicle or ointment containing an ultralowconcentration of local anesthetic in a measurable dose, whichpreparation is suitable for topical ophthalmic use.

"Subanaesthetic concentration" means concentration of local anestheticwhich produces an analgesic effect when applied topically to the corneawhere analgesia is achieved without significant loss of corneal touchsensation and without anesthesia.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is a comparative graph of average corneal sensitivity in aproparacaine treated group and in a group treated with placebo.

DETAILED DESCRIPTION OF THE INVENTION

This invention concerns a topical ophthalmic analgesic preparationconsisting essentially of a subanaesthetic concentration of a localanesthetic which is diluted enough to be nonanesthetic when appliedtopically to the cornea in gel, cream, solution, sustained releasevehicle or ointment preparation containing additionally pharmaceuticallyacceptable excipients, additives, or preservatives or othertherapeutically effective agents.

The current invention concerns a topical pharmaceutical preparationsuitable for administration of subanaesthetic ultralow concentrationsare typically from about 0.001% to about 0.05% but may exceed theconcentrations of local anesthetic for extended and sustained cornealanalgesia. Any and all concentrations of the anesthesia resulting inanalgesia but not anesthesia are intended to be within the scope of theinvention.

Local anesthetics administered topically in their typical manner atconcentrations around and above 0.5% show definite toxicity to thecornea and their use is therefore limited to short-term administration.Recently, some animal experiments in vitro and in vivo have indicatedthat low concentrations of anesthetic agents are not toxic to thecornea. The studies are described in Am. J. Ophthalmology, 99:691-696(1985), and Investigative Ophthalmology and Visual Science, 33:3029-3033(1992).

It has now been surprisingly found that ten (10) to five hundred (500)fold dilutions of the local anesthetics preparation according to theinvention provide extended and sustained analgesia to the injured ordiseased human cornea in vivo. This analgesia is achieved without lossof corneal touch sensation, that is, without inducing cornealanesthesia. Additionally, the ultralow concentrations of the localanesthetics achieve analgesia without any toxicity and withoutinterference with healing, and are therefore both highly effective inrelieving corneal pain and also safe for long term analgesia.

The preparation of the invention is formulated as a solution,suspension, gel, cream, ointment, or sustained release vehicle or usingmicrosystem, such as microdrop or microdose systems. These Microsystemsinvolve extremely small volumes of the preparation to deliver the 0.001%to 0.5% of the anesthetic and utilizing a natural propensity of the eyeto dilute these small volumes with tears. The volumes used for thismicrosystem delivery are from about 1 to about 10 μl of the solution,suspension, gel, cream, ointment or sustained release vehicle.

The Microsystems represent an alternative method of achievingnon-anesthetic and nontoxic concentrations on the eye surface usingsignificantly smaller volumes of higher concentrations (>0.05%) ofanesthetic solution. The method is described in Example 5.

The subanaesthetic concentrations used in this invention were determinedempirically, using drop volumes of approximately 30 μl. Since the volumeof the normal tear film is approximately 7 μl, some dilution of any dropoccurs when the drop is applied to the eye surface. Reflex tearinginduced by drop application would, therefore, increase this dilutioneffect.

To determine whether the eye naturally dilutes the administered dosageof the therapeutic agent, local anesthetics of the invention areadministered in up to 10 times concentrated forms in microdrops ormicrovolumes of form about 1 to about 10 μl containing from about 0.0001to about 1.0% of the anesthetics. When these small microvolumes are usedthen surface dilution due to a natural tearing becomes a significantfactor in this delivery, and the higher concentrations of anestheticachieve analgesia without anesthesia or toxicity. For example, when 1.0μl of 0.5% to 1.0% proparacaine is applied to the eye surface, a rapidten-fold dilution, more or less, occurs because of reflex tearing andformation. Thus, in this case, the effective drug concentration on theeye surface is approximately 0.05% or less proparacaine and, using thissystem, substantially the same effect is achieved as with the lessconcentrated preparations.

The analgesic solution or preparation is administered to a patientsuffering from corneal epithelial defect, whether of mechanical,inflammatory, infectious or chemical origin, caused by surgery, injury,diagnostic procedure or disease, as 1-3 volumes or an appropriate amountof sustained release vehicle, cream, ointment, gel or microsystemapplied to the eye surface as needed for the relief of pain, such asevery 5-30 minutes, every 1-6 hours, twice a day, or more or lessfrequently on an as needed basis, for as long as needed. A typicalregimen is the administration of 1 drop of 0.005% solution, that is, ofabout 1.5 μg of anesthetic, every 1-4 hours during the first day of thetreatment followed by decreasing the number of applications as theepithelial defect heals and the pain subsides.

The patient uses a drop of the ophthalmic analgesic solution or otherophthalmic analgesic preparation as often as necessary for the relief ofpain. Therefore, the actual frequency of use is usually determined bythe patient, and is dependent on the size and severity of the epithelialdefect, the rate of healing, and the patient's pain threshold. Ingeneral, the selected ophthalmic analgesic solution or preparationcontains the lowest anesthetic concentration which consistently providesrelief of pain for a patient or a population of patients. Due to itssafety because of the ultralow concentration of the anesthetic, theanalgesic solution or preparation of this invention can be used asfrequently as necessary to control pain.

Ophthalmic analgesic solutions or preparations are safe for repeatedtopical administration to the eye as often as necessary for as long asseveral months. Typically, higher concentrations, such as 0.05% ofanesthetics given at 15 minute intervals are not anesthetic. Lowerconcentrations of the anesthetics may be administered even morefrequently. The frequency of the administration to achievesubanaesthetic analgesia but not anesthesia depends on the type of theanesthetic, on the concentration of the anesthetic, and on theformulation of the anesthetic. The determination of such regimen iswithin the artisans skills. Any regimen of any topical ophthalmicanesthetic achieving subanaesthetic analgesia without anesthesia,regardless of the drug, its concentration or formulation is intended tobe within the scope of the invention.

Previous studies, described in Examples 1-4 have demonstrated that asingle dose of 0.05% topical proparacaine is subanaesthetic, that is, itdoes not cause the loss of corneal touch sensation.

Therefore, studies were designed to determined, in a double-maskedfashion, if multiple doses of 0.05% topical proparacaine aresubanaesthetic. e procedure is described in Example 6.

The results of these studies are seen in FIG. 1. FIG. 1 is a comparativegraph illustrating an average corneal sensitivity, as determined by 0.12mm esthesiometer reading in mm, after multiple doses of 0.05%proparacaine. Drops were added in 15 minute intervals for two hours. Thesame number of patients were treated with placebo. As seen in FIG. 1,although there appears to be some decrease in corneal sensation when0.05% proparacaine was applied using this system, no significantdifference between the treatment and placebo groups could bedemonstrated. At no time was corneal anesthesia induced. Therefore,multiple doses of 0.05% topical proparacaine are subanaesthetic.

In absolute amounts, the active ingredient, that is, a chosen localanesthetic, is administered in amounts from about 0.30 μg to about 15μg/per one dose. The dose is calculated as follows. The 0.005% analgesicsolution contains 50 μg of local anesthetic per 1 ml of solution. Onedrop of the commercial ophthalmic solution typically ranges from 30-70μl, however, since the maximum volume of the cul-de-sac is only 30 μl,only 30 μl of the solution is delivered to the cornea. In 1 ml of the0.005% solution (50 μg/ml), there are approximately 33 drops. In eachdrop, therefore, there is about 1.5 μg/drop of anesthetic actuallydelivered to the cornea. In less concentrated solutions of 0.0025% and0.001%, the absolute amount of anesthetic delivered to the cornea perone drop of the analgesic solution is about 0.75 μg and 0.30 μgrespectively. The concentration of the anesthetic in other ophthalmicanalgesic preparations is generally equivalent to that in the ophthalmicanalgesic solutions, and the amount of anesthetic administered via theointment, cream, gel or sustained release vehicle will be generally besimilar to that delivered by the solution.

In its broadest aspect, the invention concerns a method for alleviatingcorneal pain by administration of ophthalmic analgesic solutions orpreparations containing local anesthetic agents in a specified range ofconcentrations, such solutions or preparations to be applied topicallyin effective doses to the human cornea in vivo to safely providesustained analgesia when corneal epithelial defects are present.

In three clinical studies performed on patients with corneal epithelialdefects, the efficacy and safety of the current method and currentpreparations are demonstrated. The administration of 1 volume ofultralow concentration of anesthetic to the eye resulted in almostimmediate alleviation of pain. Repeated doses had no detrimental effecton the cornea or on the healing of the corneal epithelial defect.

In these studies, concentrations of administered anesthetic were fromabout 0.0005% to about 0.05%. In terms of absolute amount of anestheticadministered, as little as 0.15 μg per dose (0.0005%) was found to besomewhat effective analgesic in some cases. Anesthetics administered inamounts from 0.001% to 0.05% were found to be extremely effective asanalgesics for alleviation of corneal pain. The results are described indetail in three clinical studies (A, B and C) involving 38 patients (twopatients participated in two studies) who used the analgesic solutionsof the current invention to alleviate corneal pain associated withcorneal abrasion and other corneal epithelial defects.

In the first clinical study (Study A), 5 patients suffering from variousepithelial defects were treated with 10-50 times dilutions of acommercial preparation containing 0.5% (5,000 μg/ml) proparacaine. Thetested preparation contained either 500 μg/ml or 100 μg/ml ofproparacaine. The 500 μg/ml preparation was used in one patient (CaseA1) for alleviation for pain following the removal of the cornealepithelium for treatment of corneal dystrophy. Postoperatively, thepatient was given 0.05% (500 μg/ml) dosage every hour while awake forthree days. The patient reported good relief of pain. The epitheliumhealed at a normal rate, and there were no toxic reactions or adverseeffects on the cornea observed.

When the same treatment regimen was tried on the second patient (CaseA2) and compared with 0.01% (100 μg/ml) dosage, it was determined that0.05% dosage did not provide any additional pain relief. Following thetreatment with 0.01% analgesic solution, the abrasion of the secondpatient healed quickly within one day without any observable toxicreaction. Three other patients (Cases A3-5) were treated with 0.01%dosage of proparacaine using a 3 times per day or as needed regimen. Onepatient (Case A3) with chronic recurrent epithelial defects was treatedin this way for 17 days, during which time the pain was completelycontrolled, there were no signs of toxicity, and healing progressednormally and even seemed to be faster than expected.

Summarizing the results from the first study, in five patients withcorneal epithelial defects, dosages of approximately 0.01% and 0.05%proparacaine provided sustained analgesia when applied repeatedly as eyedrops. No toxicity or delay in epithelial healing was seen. In one casethe medication seemed to facilitate epithelial healing. While 0.05%proparacaine appeared to be well tolerated when used for several days inone patient, it did not appear to provide additional analgesic effectwhen compared with 0.01% proparacaine in another patient. This studyindicated the possibility that even lower concentrations than 0.01% ofthe anesthetics could provide analgesic effect.

In the second clinical study (Study B), ten patients were treated witheven more diluted analgesic preparations. In this series, three localanesthetics, lidocaine, tetracaine and proparacaine, in subanaesthetic0.005%, 0.0025%, 0.001% and 0.0005% dilutions, were tested and comparedto artificial tears solutions.

The effective analgesia and lack of corneal epithelial toxicity affordedby the 0.005% dosage was dramatically demonstrated in Case B1. Thepatient suffered from recurrent chronic epithelial defects (filamentarykeratitis) of uncertain origin. He had not responded to a variety oftopical antibiotics and artificial tears. He was treated with one dropof 0.005% proparacaine preparation, that is, with 1.5 μg ofproparacaine, every 2 hours while awake. The cornea healed completelywithin a week, with no sign of drug toxicity. After two weeks, this dosewas reduced to every 12 hours and continued for two months with thepatient reporting no pain during this time. Since the chronic epithelialdefects, previously unresponsive to various medications, had healedwhile the patient was using the analgesic preparation, it was decided tomaintain the patient on a low concentration of the analgesic. After 2months, the patient was switched to a 0.0025% dosage. One dose of 0.75μg proparacaine solution was administered every 12 hours as maintenancemedication to prevent recurrence of the chronic epithelial defects andassociated pain. After four months, the cornea remained healed with nopain or epithelial toxicity, and the 0.0025% dosage was reduced to oncea day. Corneal sensation (sensitivity to touch) remained intactthroughout the four month course of treatment.

In Case B6, a patient with pain and epithelial defects following asurgical procedure to treat a corneal epithelial dystrophy was treatedwith an analgesic preparation containing proparacaine in concentrations0.0005%, 0.001%, 0.0025%. This treatment was compared to placebotreatment with artificial tears. Slight relief from pain was observedwith analgesic preparation where the amount of the anestheticadministered to the patient was at least 0.30 μg/dose which correspondsto 0.001%. The analgesic preparations containing proparacaine 0.0025%(0.75 μg/dose) provided immediate pain reduction. Placebo and 0.0005%preparation gave no pain relief.

Overall, ophthalmic analgesic solution containing 0.005% proparacainewas very effective in reducing or eliminating pain. Preparationscontaining 0.0025% and 0.001% proparacaine were sufficiently effectiveand in some patients could be effectively substituted for the stronger0.005% preparations. Analgesic preparations containing 0.0005%proparacaine was found somewhat effective.

Ophthalmic analgesic preparations containing tetracaine in 0.0005%,0.001%, and 0.005% concentrations were studied in one case (B7) ofcorneal abrasion. A solution containing 0.005% tetracaine was found tobe very effective in suppressing the pain. The preparation containing0.001% tetracaine gave partial relief of pain, and 0.0005% tetracainehad no effect on pain.

Ophthalmic analgesic preparations containing lidocaine in 0.0005%,0.001%, 0.0025% and 0.005% concentrations were studied in two cases (B9and B10) of mechanical corneal injury. The preparation containing0.0005% lidocaine had no effect on pain. The preparations containing0.001% lidocaine in one case and 0.005% lidocaine and the other casegave rapid pain relief.

Summarizing the results of the second study, three different localanesthetics were found to be effective analgesics for topical cornealanalgesia when administered in subanaesthetic concentrations from0.0005% to 0.01%. Good pain relief was achieved in all instancestypically with 0.001% to 0.005% of proparacaine, tetracaine, andlidocaine.

In the third clinical study (Study C), 25 patients suffering from corneaabrasion (C1-C11 and C25), epithelial dystrophy (C12, C13), cornealedema (C14), dry eyes (C15), post-op pterygium (C16, C17), andphotorefractive keratectomy (C18-C24) were treated with a variety ofultralow analgesic concentrations of topical anesthetics, as seen inTable 3 and as described in Example 3.

As seen in Table 3 and as evident from the case history for eachpatient, good pain relief and healing without toxicity was achieved withbenoxinate preparation at 0.001% concentration in corneal abrasion.Benoxinate 0.0005% concentration was able to achieve a slight or partialpain relief and no dose over 0.05% was necessary to achieve good painrelief in corneal abrasion.

Summarizing the results of the third study, this study confirmed thatthe local anesthetics benoxinate, bupivacaine, proparacaine andtetracaine are effective topical analgesic agents for injured ordiseased cornea when applied in ultralow subanaesthetic concentrations.In all instances, there was a good pain relief without any sign oftoxicity to the cornea.

Summarizing results obtained in all three studies. In 9 patientssuffering from corneal abrasion, proparacaine in concentration from0.001-0.05% was sufficient to reduce pain and allow healing without anysign of toxicity. In patients suffering from epithelial dystrophy,analgesic dose between 0.01-0.05% provided sustained pain relief,decreased eyelid swelling and conjunctiva redness, and allowed healingwith no corneal toxicity. In patients suffering from corneal edema anddry eyes, the proparacaine dose of 0.02% was able to achieve good painrelief without toxicity. In the alleviation of pain in post operativepterygium, proparacaine doses between 0.03 and 0.05% achieved good painrelief, pain reduction, and healing without toxicity. Similarly,following the photorefractive keratectomy laser procedure, proparacainedoses between 0.03%-0.05% reduced pain and allowed healing withouttoxicity.

Overall, based on the above studies, clinical concentrations oflidocaine, proparacaine, benoxinate, bupivacaine and tetracaine from0.001% (10 μg/ml) to 0.05% (500 μg/ml), are effective in relieving paincaused by corneal epithelial defects. While long-term administration ofanesthetic doses of these agent are known to be toxic to the cornea, noclinical toxic effects were observed with repeated application at thesubanaesthetic concentrations. Utilization of sustained release vehiclesfor delivery of subanaesthetic dosages of the topical anestheticsachieves sufficient analgesia at even lower concentrations because ofcontinuous release of anesthetic.

In summary, in 38 patients suffering from corneal epithelial defects orinjuries, preparations of diluted benoxinate, lidocaine, bupivacaine,proparacaine, and tetracaine provided sustained analgesia when appliedrepeatedly to the eye in subanaesthetic concentration. No observed delayin epithelial healing was observed. No corneal toxic effects related tothe treatment were noted.

Additionally, during the clinical studies A-C, it has been observed thatapplanation tonometry (measurement of intraocular pressure by touchingthe eye) could not be performed in patients receiving ultralowconcentrations of local anesthetics because the treated cornea was stillsensitive to touch. This observation was contrary to the priorobservations following the administration of anesthetic dosages (0.5%and above) of the local anesthetics into the eyes, where the corneabecame completely insensitive to touch. To further explore thisobservation, two patients' corneas were treated with proparacaine0.005%, 0.01%, and 0.05% drops, prior to performing surgical proceduresthat required topical anesthesia. Corneal touch sensation was testedwith a wisp of cotton applied to the cornea after instilling eachconcentration of proparacaine. Corneal touch sensation was found to bepresent following administration of all three subanaestheticconcentrations. In contrast, when proparacaine in 0.5% anestheticconcentration was subsequently instilled on the cornea, corneal touchsensation immediately disappeared.

Based on these clinical observations, further studies which areillustrated in Example 4 were performed. From these studies, it has beenconcluded that when ultralow concentrations of local anesthetic areapplied to the cornea, analgesia is achieved without loss of cornealtouch sensation, that is, without inducing corneal anesthesia. In otherwords, subanaesthetic concentrations which are at least 10 times lowerthan anesthetic concentrations of these drugs produce an analgesic butno anesthetic effect when applied topically to the cornea.

At anesthetic concentrations, these drugs are known to cause completenerve depolarization and to block all transmission. In agreement withthis observation, and as seen in Table 4, 0.5% proparacaine depolarizedthe nerve, blocked all nerve transmission and eliminated cornealsensation.

At subanaesthetic concentrations of the topical anesthetic, the nervewas not depolarized, nerve transmission was present and cornealsensation remained. Thus, topical anesthetics administered insubanaesthetic concentrations substantially decreased or eliminated thepain but did not eliminate corneal sensation. Consequently, since thecornea was still sensitive to touch, anesthetics did not depolarize thenerve, as observed following the anesthesia, but it provides trueanalgesia which was physiologically determinable and distinguishablefrom anesthesia.

Topical Ophthalmic Preparations

In practice of the current invention, the ophthalmic analgesic solutionis prepared by diluting any local anesthetic such as proparacaine,tetracaine, lidocaine, cocaine, chloroprocaine, propoxycaine, dyclonine,pramoxine, benzocaine, procaine, hexylcaine, bupivacaine, benoxinate,mepivacaine, prilocaine, dibucaine, and etidocaine, preferablyproparacaine, lidocaine and tetracaine, commercially available. Theanesthetic is topically formulated in about 10 to 500 times diluted formas gel, cream, sustained release vehicle or ointment. Thesephysiologically compatible preparations can be made of or additionallycontain any pharmaceutically acceptable excipient, additive orpreservative such as for example sodium chloride, potassium chloride,benzalkonium chloride, boric acid, sodium borate, sodium bicarbonate,sodium sulfite, sodium acid phosphate, disodium phosphate, disodiumedetate, disodium sulfate, sodium citrate, calcium chloride, sodiumlactate, magnesium chloride, polyethylene glycol 300 and 400, povidone,carboxymethylcellulose, hydroxypropylmethylcellulose, glycerin,polyvinyl alcohol, Dextran 70, dextrose, polyquaterium 1, thimerosal,phenylmercuric nitrate, chlorbutanol, sorbic acid, hydrochloric acid orsodium hydroxide to adjust the pH, and other ophthalmologicallyacceptable agents added in concentrations which are non-toxic to thecornea. The local anesthetics and the pharmaceutically acceptableexcipients, additives or preservatives are dissolved in steriledistilled or sterile purified water to provide a solutionphysiologically compatible with the eye. The final concentration oflocal anesthetic in these new ophthalmic analgesic solutions is thusfrom about 0.001% to about 0.05%.

Additionally, these topical ophthalmic preparations are advantageouslyformulated in combination with other drugs, such as other topicalanesthetics in ultralow concentrations, analgesics, antiinflamatories,antibiotics, astringents, antiseptics, etc., and such other therapeuticagents which are typically used in topical ophthalmic preparations.

The ophthalmic analgesic preparation in the form of a cream, gel,solution, suspension, ointment, or a sustained release vehicle typicallydelivers from about 0.001% to about 0.05% local anesthetic per dose.

The above agrees with previous observations that under normalconditions, the human tear volume averages about 7 μl. The estimatedmaximum volume of the eye cul-de-sac is about 30 μl with drainagecapacity far exceeding lacrimation rate. The outflow capacityaccommodates the sudden large volume resulting from the instillation ofan eye drop or from the administration of other preparations. Mostcommercial eye drops range from 30 to 75 μl in volume. However, much inexcess of 30 μl is unable to enter the cul-de-sac and is removed bydrainage. The Microsystems of the invention utilizes natural tearing toprovide the dilution of the concentrated anesthetics into the analgesicconcentrations.

Typically, in the practice of the current invention, one volume of anophthalmic analgesic solution consisting essentially of about0.001%-0.05% of a local anesthetic as listed above, formulated in anypharmaceutically acceptable excipient physiologically compatible withthe eye surface, or formulated in other pharmaceutically acceptablevehicles and preparations, is administered repeatedly to a patient'scornea for sustained and extended pain relief.

Ophthalmic preparations of the invention, as described above, are alsoadvantageously prepared according to Remington's PharmaceuticalSciences, Chapters 87 and 92, pages 1553-1566 and 1644-1661, 17thEdition (1985) or any subsequent edition, Eds. Gennaro, R. A., et al.

Typically, suspensions and solutions are aqueous, ointments and creamstypically contain a white petrolatum-mineral oil base. Typically, theyare formulated as multidose products but may be also, for convenience,be formulated as a single dose product. The preparations are sterile andstabilized.

Ophthalmic suspensions of the invention are dispersions of a finelydivided drug substances in an aqueous vehicle containing suitablesuspending and dispersing agents as well as a suspended anesthetic insubanaesthetic concentrations from about 0.0001% to about 0.05%.

Ophthalmic concentrated suspension, such as, for example, a concentratedsuspension of the topical anesthetic, is especially suitable formicro-system preparations where the concentration of the drug is fromabout 0.001% to about 1.0% per 1-10 μl.

Ophthalmic solutions of the invention are aqueous preparations of thedrug of the invention dissolved in an appropriate aqueous solvent,typically artificial tears, saline or distilled water in concentrationfrom about 0.001%-0.05% per drop to be used directly.

Ophthalmic gels of the invention are preparations containinghigh-molecular weight polymers, additives and preservatives withadjusted pH and osmolarity to opthalmologically acceptable levels. Highmolecular weight polymers are either synthetic, such as carbomer 940(polyacrylic acid) or natural, such as hyaluronic acid or alginates. Thetopical anesthetic of the invention is formulated to contain asubanaesthetic concentration of the anesthetic per one dosage volume,such dosage preferably containing from about 0.001% to about 0.05% ofthe anesthetic.

Ophthalmic ointments or creams of the invention contain the drug fullydispensed in an ointment or cream base. In addition to the drug contentbeing from about 0.001% to about 0.05% per one dosage volume, theseointments typically contain antimicrobial agents such as chlorobutanol,parabens, substituted alcohols and phenols, or one of the organicmercurials. Care is taken that the ointment or cream does not containparticulate matter.

In addition, the agents of the invention may be formulated insustained-release vehicles where the drug is formulated such that it isreleased within a certain period of time such as 12 hours or longer. Thesustained-release vehicles may advantageously utilize reservoirs such asfor example a commercially available Ocusert implant available fromCiba-Geigy, which can deliver the drug of the invention for up to 1week. Other delivery vehicles, such as, for example, the colloidal drugdelivery systems, microcapsules, nanocapsules, macromolecular complexes,polymeric spheres, microspheres or liposomes are also intended to bewithin the scope of the invention as long as they are non-toxic andnon-irritating to the eye.

Typically, the ophthalmic formations of the invention will contain someor all of the pharmaceutically acceptable ophthalmic excipients,preservative or, additives named above, appropriate for preparation ofthe formulations for the invention. These excipients and additives arepresent in concentrations known and used in the art for ophthalmicformulations in concentrations acceptable in pharmaceutical sciences.

Ophthalmic preparations typically have neutral or slightly acidic pHbetween about pH 5 and 7.5 and are optionally buffered to maintain theproper pH throughout the extent of product shelf life. However, anyother pH at which the ophthalmic preparation of the invention may besafely administered is within the scope of the invention.

UTILITY

The ophthalmic analgesic preparations and the method of treatmentdescribed herein are useful for alleviation of pain of the eye caused bycorneal epithelial defects secondary to trauma, drying, infection,inflammation, surgery, corneal dystrophy, or other cause. The method isfast and safe and immediately causes substantial or complete relief ofpain. The analgesic solution or preparation contains ultralowconcentrations of a local anesthetic, and by repeated applications orcontinuous release safely provides sustained and extended topicalanalgesic effect on the cornea. The solution is easily prepared in asterile form, has practical shelf-life and is easy to administer.

EXAMPLE 1 Clinical Study (A) of Sustained Analgesic Effect of UltralowConcentrations of Proparacaine

This example illustrates clinical experiments and evaluation of fivepatients suffering from corneal abrasion or chronic epithelial defects.

Proparacaine hydrochloride, known under its trade name ALCAINE®, wasobtained from Alcon Laboratories as 0.5% ophthalmic solution.

The 0.5% solution of proparacaine (5,000 μg/ml) was diluted about 10:1to 0.05% or 500 μg/ml, and about 50:1 to 0.01% or 100 μg/ml, withHYPOTEARS®, a commercially available artificial tear preparation fromIolab Corporation. This was done by adding 9 drops and 2 drops ofproparacaine (39±7 μl per drop) to separate 3 ml bottles of artificialtears. These dilute proparacaine solutions were used on five patientssuffering from epithelial defects.

Case A1

Diagnosis: Surgical Corneal Abrasion for Map Dot Fingerprint CornealDystrophy

The patient's corneal epithelium was removed for treatment of adystrophy, using conventional topical anesthetic.

Postoperatively, one drop of proparacaine 0.05% (500 μg/ml) was appliedevery hour. Good relief of pain was observed within a few secondsfollowing drop administration. The 5 mm epithelial defect healed in 3days without evidence of epithelial toxicity, and without the need forpatching or oral analgesics.

Case A2

Diagnosis: Traumatic Corneal Abrasion

The patient suffered a linear corneal abrasion from paper cut. One dropof 0.01% (100 μg/ml) proparacaine solution relieved her pain within 15seconds. Further application of 0.05% (500 μg/ml) proparacaine gave noadditional relief. Therefore, she was given proparacaine 0.01% drops touse as needed. She used the drops several times a day and reported thatthe pain subsided. The abrasion healed within a day.

Case A3

Diagnosis: Filamentary Keratitis

The patient had recurrent chronic epithelial defects of uncertainetiology on the superior half of his left cornea with associated pain.These defects had not healed by application of various combinations oftopical antibiotics, steroids, artificial tears, and bandage contactlenses.

The patient was treated with ophthalmic analgesic solution. He hadimmediate relief of pain and his epithelial defects healed in a fewdays, using proparacaine 0.01% 3 times per day. After 17 days oftreatment, the cornea was still clear, with no sign of toxicity, anddrops were discontinued.

Case A4

Diagnosis: Surgical Corneal Abrasion for Map Dot Fingerprint CornealDystrophy

The patient's corneal epithelium was removed for treatment of adystrophy, using conventional topical anesthetic.

Postoperatively, patching was poorly tolerated, and 2 days after surgerythe patient had a 5 mm epithelial defect with moderate pain. The eye wastreated with proparacaine 0.01% 3 times daily. No pain was reported, andexamination 2 days later revealed a healed cornea with no sign oftoxicity.

Case A5

Diagnosis: Surgical Corneal Abrasion for Band Keratopathy

The patient's corneal epithelium was removed for treatment of calcificband keratopathy.

The epithelium healed partially with patching over 3 days. Two smallepithelial defects remained. Patching was discontinued.

The patient was given proparacaine 0.01% drops to use as needed forpain. The cornea was healed by the return visit 3 days later. The dropshad given adequate relief of pain.

                                      TABLE 1                                     __________________________________________________________________________    CLINICAL EVALUATION OF ANALGESIC EFFECT OF PROPARACAINE                                        CONCEN-                                                      CASE                                                                              DIAGNOSIS                                                                           ANESTHETIC                                                                           TRATION                                                                             REGIMEN   RESULTS                                      __________________________________________________________________________    A1  Abrasion                                                                            Proparacaine                                                                         0.05% 3 days/every hour                                                                       Healed                                                                        Good pain relief                             A2  Abrasion                                                                            Propanacaine                                                                         0.01% 1 day/as needed                                                                         Healed                                                        0.05%           Good pain relief                                                              with .01% & .05%                             A3  Filamentary                                                                         Proparacaine                                                                         0.01% 17 days/3 times a day                                                                   Healed in 17 days                                Keratitis                    Good pain relief                                                              No toxicity                                  A4  Abrasion                                                                            Proparacaine                                                                         0.01% 2 days/3 times a day                                                                    Healed in 2 days                                                              Good pain relief                             A5  Abrasion                                                                            Proparacaine                                                                         0.01% 3 days/as needed                                                                        Healed in 3 days                                                              Good pain relief                             __________________________________________________________________________

In summary, in five patients with corneal epithelial defects, solutionsof approximately 0.01% and 0.05% proparacaine provided sustainedanalgesia when applied repeatedly as eye drops. No toxicity or delay inepithelial healing was seen, and in case A3 the medication possiblyfacilitated epithelial healing. While 0.05% proparacaine appeared to bewell tolerated when used for several days in one patient, it did notappear to provide additional analgesic effect when compared with 0.01%proparacaine in another patient.

In the same manner the anesthetics are formulated as gel, cream,suspension, ointment or in a sustained release vehicle.

EXAMPLE 2 Clinical Study (B) of Sustained Analgesic Effect of UltralowConcentration of Local Anesthetics

This example illustrates clinical experiments and evaluation of tenpatients receiving ophthalmic analgesic solutions of variousconcentrations.

Solutions

Lidocaine hydrochloride was obtained from Abbott Laboratories as 1.0%solution for injection.

Proparacaine hydrochloride, known under its trade name ALCAINE®, wasobtained from Alcon Laboratories as 0.5% ophthalmic solution.

Tetracaine hydrochloride was obtained from Iolab Corporation as 0.5%ophthalmic solution.

Using a tuberculin syringe and a 30 g needle to allow accurate dilutionwith HYPOTEARS®, a commercially available artificial tear preparationfrom Iolab Corporation, solutions of lidocaine, proparacaine, andtetracaine were prepared at various concentrations. Double dilutiontechniques were used to make optimum use of the tuberculin syringecalibration. These solutions were given the generic name "Turbotears™",and were designated as follows:

    ______________________________________                                        Turbotears ™                                                               ______________________________________                                        L1          Lidocaine 0.005% (50 μg/ml) in artificial                                  tears                                                             L2          Lidocaine 0.0025% (25 μg/ml) in artificial                                 tears                                                             L3          Artificial tears                                                  L4          Lidocaine 0.001% (10 μg/ml) in artificial                                  tears                                                             L5          Lidocaine 0.0005% (5 μg/ml) in artificial                                  tears                                                             P1          Proparacaine 0.005% (50 μg/ml) in artificial                               tears                                                             P2          Proparacaine 0.0025% (25 μg/ml) in artificial                              tears                                                             P3          Artificial tears                                                  P4          Proparacaine 0.001% (10 μg/ml) in artificial                               tears                                                             P5          Proparacaine 0.0005% (5 μg/ml) in artificial                               tears                                                             T1          Tetracaine 0.005% (50 μg/ml) in artificial                                 tears                                                             T2          Tetracaine 0.0025% (25 μg/ml) in artificial                                tears                                                             T3          Artificial tears                                                  T4          Tetracaine 0.001% (10 μg/ml) in artificial                                 tears                                                             T5          Tetracaine 0.0005% (5 μg/ml) in artificial                                 tears                                                             ______________________________________                                    

The following patients with corneal epithelial defects were treated withTurbotears™ solutions:

Case B1

Diagnosis: Filamentary Keratitis

Case B1 describes treatment of the same patient as described in Case A3,Example 1. The patient had recurrent chronic epithelial defects ofuncertain etiology. Symptoms recurred within 2 weeks of discontinuingthe treatment described in Study A (Case A3). Subsequently, the patientcontinued to have recurrent episodes of epithelial breakdown and pain,with variable response to lubricating agents (artificial tears).

After five months of recurrent disease, the patient was restarted on anophthalmic analgesic solution. Turbotears™ solution P1 containing 0.005%proparacaine was initially used every 2-3 hours to control pain. Oneweek later, the cornea was completely healed. After 2 weeks oftreatment, the dose was reduced to every 12 hours, and the cornearemained healed after two months of continuous treatment, with no signof drug toxicity. The patient was then switched to Turbotears™ P2(0.0025% proparacaine) every 12 hours, as maintenance medication, for 2additional months. At that time, after four total months of treatment,the cornea remained healed without no evidence of toxicity, and thepatient remained pain-free. Turbotears™ P2 was then tapered to once aday as maintenance medication. While the pain was completely controlled,corneal sensation (sensitivity to touch) remained intact throughout thefour month course of treatment.

Case B2

Diagnosis: Corneal Abrasion

The patient suffered a corneal abrasion following contact lens use. Hewas asked to compare Turbotears™ P1 (0.005% proparacaine) and ananalgesic solution containing proparacaine 0.01% for the relief of pain.Both drops provided good pain relief. The typical interval between dropsfor either concentration was 1-2 hours, although occasionally eitherdrop was needed 10-30 minutes apart. Pain subsided and analgesicsolutions were discontinued after two days. Examination after four daysrevealed the cornea completely healed with no evidence of drug toxicity.

Case B3

Diagnosis: Epithelial defect following removal of corneal foreign body

The patient's cornea was drilled to remove a metal foreign body.

After surgery, the patient was given Turbotears™ P1 (0.005%proparacaine) to use as needed for pain. He was comfortable and withoutpain using the drops every four hours while awake, with epithelialhealing occurring in less than 24 hours.

Case B4

Diagnosis: Epithelial defect following removal of corneal foreign body

The patient's cornea was drilled to remove a metal foreign body.

After the surgery, the patient was given Turbotears™ P1 containing0.005% of proparacaine to use as needed for pain. She was comfortableusing the drops every 1-2 hours until bedtime, and had no further painthe next day.

Case B5

Diagnosis: Rosacea

The patient suffered debilitating pain from microscopic cornealepithelial defects in one eye from ocular rosacea.

Turbotears™ P1 (0.005% proparacaine) gave him good relief of pain forseveral hours after each dose, and he was able to return to work. He wasalso treated with oral antibiotics for rosacea. Ten days later thecornea was completely healed without any sign of drug toxicity.

Case B6

Diagnosis: Corneal Epithelial Dystrophy

The patient had pain and corneal epithelial defects following anteriorstromal puncture, a procedure to treat a corneal epithelial dystrophy.In an office trial, he was given Turbotears™ P2, P3, P4, and P5,containing proparacaine 0.0025%, placebo, 0.001%, and 0.0005%respectively, to compare for the relief of pain. P3 and P5 (0.0005%) hadno effect. P4 (0.001%) had a slightly beneficial effect. P2 (0.0025%)provided immediate and significant reduction in pain and sensitivity tolight. Therefore, the patient was given P2 (0.0025%) drops to use athome. Good pain relief was achieved by using the drops every 1-3 hourswhile awake for 5 days. The epithelium healed without evidence of drugtoxicity.

Case B7

Diagnosis: Traumatic Corneal Abrasion

The patient was poked in the eye with a toy and presented with cornealabrasion and pain. In an office trial, she was given Turbotears™ T1, T2,T3, T4, and T5, containing tetracaine 0.005%, 0.0025%, placebo, 0.001%,and 0.0005% respectively, to compare for the relief of pain. T4 dropsappeared to give some relief of pain, and therefore, the patient wasgiven T4 drops to use at home. However, she returned the next day withsignificant residual pain despite using the drops every 30 minutes.Therefore, she was given T1 drops (tetracaine 0.005%) to use at home.The patient used the drops every 1-4 hours while awake with good reliefof pain. Follow-up examination six days later showed the corneawell-healed with no evidence of drug toxicity.

Case B8

Diagnosis: Traumatic Corneal Abrasion

The patient scratched his cornea with a steel peg. He presented withpain and corneal abrasion. In an office trial, he was given Turbotears™P2, P3, P4, and P5, containing proparacaine 0.0025%, placebo, 0.001%,and 0.0005% respectively, to compare for the relief of pain. P3 and P5(0.0005%) had minimal effect. P4 (0.001%) was effective in reducingpain. Therefore, the patient was given P4 (0.001%) drops to use at home.Good pain relief was achieved by using the drops every thirty minutes tonine hours while awake over the next two days. After two days, thecornea was well-healed with no evidence of drug toxicity.

Case B9

Diagnosis: Traumatic Corneal Abrasion

The patient's eye was scratched by a branch and he presented with asmall corneal abrasion and moderate pain. In an office trial, he wasgiven Turbotears™ L2, L3, L4, and L5, containing lidocaine 0.0025%,placebo, 0.001%, and 0.0005% respectively, to compare for the relief ofpain. L3 (placebo) and L5 (0.0005%) had no significant effect. L4(0.001%) appeared to make the patient comfortable. The patient reportedthat he used one drop of L4 that evening to control pain, with immediaterelief. The cornea was examined one week later and found to bewell-healed with no evidence of drug toxicity.

Case B10

Diagnosis: Traumatic Corneal Abrasion

The patient scratched her cornea with a plant while gardening. She wasinitially evaluated and patched at another facility. The following dayshe was referred with persistent severe pain and corneal abrasion. In anoffice trial, she was given Turbotears™ L1, L2, L3, L4, and L5,containing lidocaine 0.005%, 0.0025%, placebo, 0.001%, and 0.0005%respectively, to compare for the relief of pain. L3 (placebo), L4(0.001%), and L5 (0.0005%) had no significant effect. L2 (0.0025%)appeared to give some pain relief, although the eye still feltuncomfortable. L1 (0.005%) provided significant pain reduction.Therefore, the patient was given L1 (0.005%) drops to use at home. Sheused the drops every 20 minutes to five hours while awake over the firstday, with some foreign body sensation, but the pain was dramaticallydecreased. The patient, previously debilitated by pain, was able toreturn to her normal activities. On the second day, only two doses ofanalgesic solution were needed to control the pain completely. After twodays, the cornea was healed with no sign of drug toxicity.

                                      TABLE 2                                     __________________________________________________________________________    CLINICAL EVALUATION OF ANALGESIC                                              EFFECT OF LIDOCAINE, PROPARACAINE, AND TETRACAINE                                              CONCEN-                                                      CASE                                                                              DIAGNOSIS                                                                           ANESTHETIC                                                                           TRATION                                                                             REGIMEN   RESULTS                                      __________________________________________________________________________    B1  Filamentary                                                                         Proparacaine                                                                         0.005%                                                                              4 months/ Good pain relief                                 Keratitis    .0025%                                                                              tapered from 2-3                                                                        Healed                                                              hours to once a day                                                                     No toxicity                                                                   No recurrence                                B2  Abrasion                                                                            Proparacaine                                                                         0.01% 2 days/every 10 mins.                                                                   Good pain relief                                              0.005%                                                                              to 2 hours                                                                              with .01% and                                                                 .005%.                                                                        Healed                                                                        No toxicity                                  B3  Epithelial                                                                          Proparacaine                                                                         0.005%                                                                              1 day/every 4 hours                                                                     Good pain relief                                 Defect                       Healed                                       B4  Epithelial                                                                          Proparacaine                                                                         0.005%                                                                              1 day/every 1-2 hours                                                                   Good pain relief                                 Defect                       Healed                                       B5  Ocular                                                                              Proparacaine                                                                         0.005%                                                                              several days                                                                            Good pain relief                                 Rosacea            few times/day                                                                           Healed                                       B6  Epithelial                                                                          Proparacaine                                                                         0.0005%                                                                             --        No effect                                        Dystrophy    0.001%                                                                              --        Slight decrease in                                                            pain                                                          0.0025%                                                                             5 days/every 1-3                                                                        Good pain relief                                                    hours     Healed                                                                        No toxicity                                  B7  Abrasion                                                                            Tetracaine                                                                           0.0005%         No effect                                                     0.001%                                                                              1 day/every 30 mins.                                                                    Partial pain relief                                           0.005%                                                                              2 day/every 1-4 hours                                                                   Good pain relief                                                              Healed                                       B8  Abrasion                                                                            Proparacaine                                                                         0.0005%                                                                             --        Minimal effect                                                0.001%                                                                              2 days/every 30 mins.                                                                   Good pain relief                                                    to 9 hours                                                                              Healed                                       B9  Abrasion                                                                            Lidocaine                                                                            0.0005%                                                                             --        No effect                                                     0.001%                                                                              1 day /1 dose                                                                           "Instant" pain                                                                relief                                                                        Healed                                       B10 Abrasion                                                                            Lidocaine                                                                            0.0005%                                                                             --        No effect                                                     0.001%                                                                              --        No effect                                                     0.0025%                                                                             --        Partial pain relief                                           0.005%                                                                              2 days/every 20 mins.                                                                   Good pain relief                                                    to 5 hours                                                                              Healed                                       __________________________________________________________________________

In summary, in ten patients with corneal epithelial defects, dilutesolutions of lidocaine, proparacaine, and tetracaine provided sustainedanalgesia when applied repeatedly as eye drops. There was no delay inepithelial healing. No toxic effects were noted after as long as 4months of treatment.

In the same manner the anesthetics are formulated as gel, cream,suspension, ointment or in a sustained release vehicle.

EXAMPLE 3 Clinical Study (C) of Sustained Analgesia Effects of UltralowConcentrations of Local Anesthetics

This example illustrates clinical experiments and evaluation of 25patients (C1-C25) receiving various ophthalmic analgesic solutions ofvarious concentrations.

This example includes four types of corneal epithelial defects notpresented in Examples 1 and 2. Dry eye causes microerosions of thecorneal epithelium, with chronic pain. Corneal edema causes swelling ofthe epithelial cells, with resultant pressure on nerve endings and microand macro epithelial erosions or defects. In pterygium surgery andphotorefractive keratectomy (PRK), the surface epithelium and anteriorstromal layer of the cornea are removed, creating epithelial defectswhich heal over several days.

Solutions

Benoxinate hydrochloride was obtained from Barnes Hind Pharmaceuticalsin a 0.4% solution as the anesthetic agent in Fluoress®, a 0.25%fluorescein solution.

Bupivacaine hydrochloride, preservative free, known under its trade nameSENSORCAINE-MPF™, was obtained from Astra Pharmaceutical Products as0.5% solution for injection.

Proparacaine hydrochloride, known under its trade name ALCAINE®, wasobtained from Alcon Laboratories, Fort Worth, Tex., as 0.5% ophthalmicsolution.

Tetracaine hydrochloride was obtained from Iolab Corporation as 0.5%ophthalmic solution.

Using a tuberculin syringe and a 30 g needle to allow accurate dilutionwith HYPOTEARS®, a commercially available artificial tear preparationfrom Iolab Corporation, solutions of benoxinate, bupivacaine,proparacaine, and tetracaine were prepared at various concentrations.These solutions were given the generic name "Turbotears™" and weredesignated as follows:

    ______________________________________                                        Turbotears ™                                                               ______________________________________                                        B1          Benoxinate 0.005% (50 μg/ml) in artificial                                 tears                                                             B2          Benoxinate 0.0025% (25 μg/ml) in artificial                                tears                                                             B3          Artificial tears                                                  B4          Benoxinate .001% (10 μg/ml) in artificial                                  tears                                                             B5          Benoxinate .0005% (5 μg/ml) in artificial                                  tears                                                             B.01%       Benoxinate .01% (100 μg/l) in artificial tears                 B.02%       Benoxinate .02% (200 μg/l) in artificial tears                 BU1         Bupivacaine 0.005% (50 μg/ml) in artificial                                tears                                                             BU2         Bupivacaine 0.0025% (25 μg/ml) in artificial                               tears                                                             BU.01%      Bupivacaine 0.01% (100 μg/ml) in artificial                                tears                                                             BU.05%      Bupivacaine 0.05% (500 μg/ml) in artificial                                tears                                                             P1          Proparacaine 0.005% (50 μg/ml) in artificial                               tears                                                             P2          Proparacaine 0.0025% (25 μg/ml) in artificial                              tears                                                             P3          Artificial tears                                                  P4          Proparacaine 0.001% (10 μg/ml) in artificial                               tears                                                             P5          Proparacaine 0.0005% (5 μg/ml) in artificial                               tears                                                             P.01%       Proparacaine 0.01% (100 μg/ml) in artificial                               tears                                                             P.02%       Proparacaine 0.02% (200 μg/ml) in artificial                               tears                                                             P.03%       Proparacaine 0.03% (300 μg/ml) in artificial                               tears                                                             P.05%       Proparacaine 0.05% (500 μg/ml) in artificial                               tears                                                             T1          Tetracaine 0.005% (50 μg/ml) in artificial                                 tears                                                             T2          Tetracaine 0.0025% (25 μg/ml) in artificial                                tears                                                             T3          Artificial tears                                                  T4          Tetracaine 0.001% (10 μg/ml) in artificial                                 tears                                                             ______________________________________                                    

The following patients were treated to test the safety and efficacy ofthese Turbotears™ solutions:

Case C1

Diagnosis: Corneal Abrasion

The patient suffered a corneal abrasion following contact lens use. Inan office trial, Turbotears™ B5, B4 and B3 had no significant analgesiceffect. Turbotears™ B2 (0.0025% benoxinate) and B1 (0.005% benoxinate)gave progressively greater pain relief. The patient used the lattersolution 31 times over the next two days, typically every 10-30 minuteswhile awake. Pain was controlled and the epithelium was well-healed byday 3, without evidence of toxicity.

Case C2

Diagnosis: Corneal Abrasion

The patient awoke with pain and corneal abrasion. Turbotears B2 (0.0025%benoxinate) and B0.01% (0.01% benoxinate) gave only slight pain reliefin an office trial. Higher concentrations were not tried.

Case C3

Diagnosis: Traumatic Corneal Abrasion

The patient suffered corneal abrasion when hit in the left eye with atoy. In an office trial, Turbotears™ B3 (artificial tears) gave norelief of pain. Turbotears™ B5 (0.0005% benoxinate) had only slightanalgesic effect. Turbotears™ B4 (0.001% benoxinate) and B2 (0.0025%benoxinate) were more effective, subjectively reducing pain 50%.Turbotears™ B1 (0.005% benoxinate) reduced pain 80%, and was thereforeused 11 times over the next 5 hours with good pain relief. However, thatnight the patient's pain persisted, and therefore he was givenTurbotears™ B0.01% (0.01% benoxinate). He had immediate pain relief andwas able to sleep. He used 3 doses the next morning over 2 hours and hehad no further pain. The cornea healed without delay or toxicity.

Case C4

Diagnosis: Traumatic Corneal Abrasion

A piece of paper scratched the patient's right cornea. Patching was nottolerated. Turbotears™ B3 (artificial tears) had no effect. TurbotearsB5 (benoxinate 0.0005%) provided partial pain relief. Both B4(benoxinate 0.001%) and B2 (benoxinate 0.0025%) eliminated her pain. Thepatient used Turbotears™ B2 every 1 to 3 hours that day and once thefollowing morning. She had good pain relief, and the cornea wascompletely healed when examined 3 days later.

Case C5

Diagnosis: Traumatic Corneal Abrasion

A tree branch scratched the patient's right cornea. Turbotears B0.01%(benoxinate 0.01%) was used every 1/2 hour for about 6 hours, but onlyrelieved the pain for the first hour. Therefore, B0.02% (benoxinate0.02%) was substituted. Application every 1/2 hour provided goodanalgesia for the rest of the day.

The drops were used once the following morning, and the patient had nofurther pain. His cornea healed without sequelae.

Case C6

Diagnosis: Epithelial Defect Following Removal of Corneal Foreign Body

The patient's cornea was drilled to remove a metal foreign-body.

After the surgery, the patient was given Turbotears™ B3 (artificialtears), B1 (0.005% benoxinate) and B2 (0.0025% benoxinate). B3 was of nobenefit. B1 and B2 gave equal analgesic effect, used every 10 minutes to2 hours the first day. The drops were used 3 times on day 2, once on day3, and the patient was pain-free on day 4.

Case 7

Diagnosis: Traumatic Corneal Abrasion

The patient was hit in the left eye with a dog biscuit and sufferedcorneal abrasion. Turbotears™ B1 (0.005% benoxinate) was the lowestconcentration that gave satisfactory pain relief. She used the drops 16times on day 1, 11 times on day 2, and twice on days 3 and 4. The corneawas well-healed when examined on day 9.

Case C8

Diagnosis: Traumatic Corneal Abrasion

The patient was kicked in the left eye by a 2 year old child. He wasseen with persistent corneal abrasion and pain after 2 days of patchingand vicodin (narcotic oral pain medication). Turbotears™ BUl (0.005%bupivacaine) and BU2 (0.0025% bupivacaine) had limited analgesic effect.Turbotears™ BU0.01% (0.01% bupivacaine) and BU0.05% (0.05% bupivacaine)gave progressively greater analgesic effect. The patient usedTurbotears™ BU0.05% 15 times in the next 24 hours, with good painrelief. He was also treated with a bandage contact lens and antibioticdrops. His cornea healed without toxic effects.

Case C9

Diagnosis: Traumatic Corneal Abrasion

The patient was initially treated elsewhere with antibiotic and patchfor a traumatic corneal abrasion (a finger poked his right eye). Thefollowing day the patient had significant pain and photophobia withpartial healing of the epithelium. Patching was discontinued, and thepatient used Turbotears™ P0.05% (0.05% proparacaine) every 45-60 minutesfor the next 12 hours with excellent relief of pain. He was pleasedbecause he could open his eye and work. The patient was pain-free andthe cornea well-healed by the following day.

Case C10

Diagnosis: Surgical Corneal Abrasion for Map Dot Fingerprint CornealDystrophy

The patient's corneal epithelium was removed for treatment of adystrophy, using conventional topical anesthetic. Pain was controlled inthe first 24 hours with patch and oral pain medication. In a officetrial, Turbotears™ P3 (artificial tears) had no effect. Turbotears™ P1(0.005% proparacaine) provided significant analgesia. Comfort wasmaintained with 6 drops on day 1, 2 drops on day 2, and 1 drop on day 3.The epithelial defect was healed when the patient was examined on day 4.One month later the cornea was clear with 20/20 vision.

Case C11

Diagnosis: Traumatic Corneal Abrasion

The patient suffered a corneal abrasion when a dog scratched her lefteye. She used Turbotears™ P0.05% (proparacaine 0.05%) every 1 to 5 hourswhile awake over the next 2 days. The drops reduced her pain and allowedher to open her eye. The cornea was well-healed without toxicity whenexamined 4 days later.

Case C12

Diagnosis: Epithelial Defect Secondary to Map Dot Fingerprint Dystrophy

The patient developed a large corneal epithelial defect secondary to mapdot fingerprint corneal dystrophy. He used Turbotears™ P0.01%(proparacaine 0.01%) 1 to 2 times per day over the next 3 days. Heclaimed the drops gave him sustained and substantial pain relief. Theabrasion was well-healed when checked 6 days later.

Case C13

Diagnosis: Corneal Abrasion With Map Dot Fingerprint Corneal Dystrophy

The patient suffered corneal abrasion secondary to corneal dystrophy.She was given Turbotears™ P0.05% (0.05% proparacaine). She used thedrops 14 times from 2 p.m. to 10 p.m. Pain was controlled, but shenoticed progressive conjunctival and eyelid swelling. The pain was muchless the following day, and therefore the Turbotears™ were discontinued,as the redness and swelling concerned the patient. Despite what wasprobably an allergic reaction, the cornea was well-healed withoutevidence of toxicity when examined on day 5.

Case C14

Diagnosis: Corneal Epithelial Edema

The patient developed corneal epithelial swelling or edema after thevitreous gel contacted the endothelium, or inner "pump" layer of thecornea, following eye surgery. This epithelial edema caused chronic painand photophobia (light sensitivity). The patient was given Turbotears™P0.02% (0.02% proparacaine). Over the next 17 days, the patient achievedgood pain relief using 93 doses of Turbotears™ , sometimes as often as15 minutes apart. The corneal edema resolved with further eye surgery,and no toxic effects on the epithelium were seen.

Case C15

Diagnosis: Micro-epithelial Defects Secondary to Dry Eyes

Insufficient tears led to microscopic erosions, or defects, of thecorneal epithelium, with chronic pain and redness. Artificial tears didnot relieve her symptoms. The patient used Turbotears™ P0.02% (0.02%proparacaine) 2 to 4 times per day over the next 2 weeks. She was happyand pleasantly surprised with decreased redness and no pain. There wasno evidence of corneal toxicity.

Case 16

Diagnosis: Corneal Epithelial Defect Following Pterygium Surgery

One day after pterygium surgery, the patient had a large residualepithelial defect. She was nauseated from oral pain medication.

In an office trial, Turbotears™ P0.03% (0.03% proparacaine) were theminimal strength to relieve her pain. The drops provided analgesia forabout 15 minutes when she had pain at night. She used 15 doses over thenext 2 days, when her cornea was seen to be healed without toxicity.

Case C17

Diagnosis: Corneal Epithelial Defect Following Pterygium Surgery

One day after pterygium surgery, the patient had a moderate-sizedresidual epithelial defect. He used Turbotears™ P0.05% (proparacaine0.05%) every 1 to 3 hours while awake for the next 5 days. Pain wassignificantly reduced by the drops. The cornea healed without evidenceof toxicity.

Cases 18-24

Diagnosis: Corneal Epithelial Defect Following PhotorefractiveKeratectomy (PRK)

Photorefractive keratectomy (PRK) is a laser procedure in which thecorneal surface is reshaped to correct nearsightedness (myopia). Theresulting corneal epithelial defect usually heals in 3-4 days.

A pilot analgesia study performed in April 1993 indicated thatTurbotears™ P0.01% (0.01% proparacaine) was ineffective in providingsignificant analgesia for post-op PRK patients. In the same studyproparacaine 0.03% seemed to be effective. Turbotears™ concentrationswere selected for the following 7 patients based on this pilot study.

These 7 patients underwent PRK for correction of myopia. All 7 were fitwith bandage soft contact lenses post-operatively to promote comfort andepithelial healing. However, all 7 experienced significantpost-operative pain not relieved by voltaren drops. One patient wasgiven Turbotears™ P0.03% (0.03% proparacaine). Four patients were givenTurbotears™ P0.05% (0.05% proparacaine). Two patients were given bothP0.05% and BU0.05% (bupivacaine 0.05%). All seven patients hadsignificant pain relief with each of their respective Turbotears™solutions, used for 1 to 3 days. No corneal toxicity was seen.

Case C25

Diagnosis: Traumatic Corneal Abrasion

The patient suffered a corneal abrasion when debris from a bush flewinto his eye. The following Turbotears™ solution were tried in theoffice: T3 (artificial tears) had no analgesic effect. T1 (0.005%tetracaine) and T2 (0.0025% tetracaine) provided significant painrelief, compared to the minimal effect of T4 (0.001% tetracaine). Thepatient use Turbotears™ T1 every 30 minutes to 2 hours that afternoonand the next morning. He noted good pain relief for 15 minutes, followedby slow return of pain. The abrasion was healed when examined 4 dayslater.

                                      TABLE 3                                     __________________________________________________________________________    CLINICAL EVALUATION OF ANALGESIC EFFECT OF BENOXINATE,                        BUPIVACAINE, PROPARACAINE AND TETRACAINE                                                       CONCEN-                                                      CASE                                                                              DIAGNOSIS                                                                           ANESTHETIC                                                                           TRATION                                                                             REGIMEN   RESULTS                                      __________________________________________________________________________    C1  Abrasion                                                                            Benoxinate                                                                           0.005%                                                                              3 days/   Good pain relief                                                    10-30 min Healed                                                              for 2 days                                                                              No toxicity                                  C2  Abrasion                                                                            Benoxinate                                                                           0.01% 1 time    Only slight                                                   0.0025%                                                                             1 time    analgesic effect                             C3  Abrasion                                                                            Benoxinate                                                                           0.0005%                                                                             2 days/   Slight pain relief                                            0.0025%                                                                             11 times in                                                                             50% pain relief                                               0.005%                                                                              5 hours   Comfortable until                                                   At bedtime                                                                              night                                                         0.01%           Good pain relief                                                              Healed                                                                        No toxicity                                  C4  Abrasion                                                                            Benoxinate                                                                           0.0005%                                                                             2 days    Partial pain relief                                           0.001%                                                                              every 1-3 hours                                                                         Good pain relief                                              0.0025%         Healed                                                                        No toxicity                                  C5  Abrasion                                                                            Benoxinate                                                                           0.01% 1 day/every 30 mins.                                                                    Pain relief for                                                     for 6 hours                                                                             first hour                                                    0.02%           Good pain relief                                                              Healed                                                                        No toxicity                                  C6  Abrasion                                                                            Benoxinate                                                                           0.0025%                                                                             3 days/every                                                                            Good pain relief                                              0.005%                                                                              10 mins. to 2 hrs.                                                                      Healed                                                              on day 1, No toxicity                                                         3× on day 2,                                                            and 1× on day 3                                  C7  Abrasion                                                                            Benoxinate                                                                           0.005%                                                                              4 days/   Good pain relief                                                    16× on day 1/                                                                     Healed                                                              11× on day 2/                                                                     No toxicity                                                         2× on days 3 & 4                                 C8  Abrasion                                                                            Bupivacaine                                                                          0.0025%                                                                             1 day/15×                                                                         Limited pain relief                                           0.005%          Limited pain relief                                           0.05%           Good pain relief                                                              Healed                                                                        No toxicity                                  C9  Abrasion                                                                            Proparacaine                                                                         0.05% 1 day/    Good pain relief                                                    every 45-60 minutes                                                                     Healed                                                                        No toxicity                                  C10 Abrasion                                                                            Proparacaine                                                                         0.005%                                                                              4 days/up to 6                                                                          Good pain relief                                                    times per day                                                                           Healed                                                                        No toxicity                                  C11 Abrasion                                                                            Proparacaine                                                                         0.05% 2 days/every                                                                            Pain reduced                                                        1-5 hrs.  Healed                                                              for 2 days                                                                              No toxicity                                  C12 Epithelial                                                                          Proparacaine                                                                         0.01% 3 days/1-2×                                                                       Sustained pain relief                            Dystrophy          per day   Healed                                                                        No toxicity                                  C13 Epithelial                                                                          Proparacaine                                                                         0.05% 1 day/    Pain controlled                                  Dystrophy          14× over 8 hrs.                                                                   Eyelid swelling,                                                              conjunctiva red                                                               decreased                                                                     Cornea healed                                                                 No corneal toxicity                          C14 Corneal                                                                             Proparacaine                                                                         0.02% 17 days/93 doses/                                                                       Good pain relief                                 edema              15 mins   No toxicity                                  C15 Dry eyes                                                                            Proparacaine                                                                         0.02% 2 weeks/2-4×                                                                      Good pain relief                                                    per day   Less redness                                 C16 Post-op                                                                             Proparacaine                                                                         0.03% 2 days/15×                                                                        Good pain relief                                 pterygium                    Healed                                                                        No toxicity                                  C17 Post-op                                                                             Proparacaine                                                                         0.05% 5 days/every                                                                            Pain reduced                                     pterygium          1-3 hrs.  Healed                                                                        No toxicity                                  C18-24                                                                            Post-op                                                                             Proparacaine                                                                         0.03% 1-3 days/as needed                                                                      Good pain relief                                 PRK          0.05%           All healed                                             Bupivacaine                                                                          0.05%           No toxicity                                  C25 Abrasion                                                                            Tetracaine                                                                           0.001%                                                                              4 days/   Minimal effect                                                0.0025%                                                                             every 30 mins                                                                           Good pain relief                                              0.005%                                                                              to 2 hours                                                                              Healed                                                                        No toxicity                                  __________________________________________________________________________

In the same manner the anesthetics are formulated as gel, cream,suspension, ointment or in a sustained release vehicle.

EXAMPLE 4 Subanaesthetic Concentrations of Local Anesthetics for TopicalCorneal Analgesia

This example demonstrates that the ultralow concentrations of localanesthetics used on corneal epithelial defects for analgesia aresubanaesthetic concentrations of the local anesthetics.

A Luneau anesthesiometer was used to quantify corneal sensation afterapplication of ultralow concentrations of proparacaine. The instrumentwas calibrated from 0 to 6, with 0 indicating complete absence ofcorneal sensation, and 6 indicating the greatest sensitivity to touch.

Controls

Three normal volunteers were used as controls. One eye was tested ineach of three volunteers. The sequence of drops applied to the eye was:placebo (Hypotears), proparacaine 0.005%, 0.01%, 0.03%, 0.05%, and 0.5%.Corneal sensation was tested on minute after each drop was applied. Therespective anesthesiometer readings were 5 (placebo), 5 (proparacaine0.005%), 5 (proparacaine 0.01%), 5 (proparacaine 0.03%), 4 (proparacaine0.05%), and 0 (proparacaine 0.5% anesthetic concentration) (normal eye1); 3.5 (placebo), 3.5 (proparacaine 0.005%), 4.0 (proparacaine 0.01%);3.0 (proparacaine 0.03%), 3.0 (proparacaine 0.05%) and 0 (normal eye 2);and 5 (placebo), 5 (proparacaine 0.005%), 5 (proparacaine 0.01%), 4.5(proparacaine 0.0:3%), 4.5 (proparacaine 0.05%) and 0 (proparacaine0.5%) (normal eye 3).

Case 1 - Corneal Abrasion

One patient with a painful corneal abrasion was given proparacaine 0.05%with good pain relief. Anesthesiometer reading after a single drop was4.

Case 2 - Keratitis

A 75 year old lady with painful keratitis (inflammation of the cornea)of the left eye was given the same series of proparacaine drops in theleft eye as noted above. Anesthesiometer readings were 5 (placebo), 5(proparacaine 0.005%), 4.5 (proparacaine 0.01%), 4.0 (proparacaine0.03%), 3.0 (proparacaine 0.03%), and 0 (proparacaine 0.5%).

Case 3 - Corneal Abrasion

A 45 year old firefighter with painful bilateral corneal erosions wasgiven the same series of drops in each eye. His anesthesiometer readingswere 4.0 (placebo), 5.0 (proparacaine 0.005%), 4.5 (proparacaine 0.01%),4.5 (proparacaine 0.03%), 5.0 (proparacaine 0.05%), and 0 (proparacaine0.5%) (right eye); and 6.0 (placebo), 5.0 (proparacaine 0.005%), 5.5(proparacaine 0.01%), 5.0 (proparacaine 0.03%), 4.5 (proparacaine0.05%), and 0 (proparacaine 0.5%) (left eye).

In summary, in all cases when ultralow subanaesthetic concentrations ofproparacaine were administered, corneal sensation was present, but wasabsent when the anesthetic concentration (0.5%) of proparacaine wasapplied. The results observed for this group of 6 patients are compiledin Table 4.

                  TABLE 4                                                         ______________________________________                                        Anesthesiometer Readings                                                      PATIENT   0.000%  0.005%  0.01% 0.03% 0.05% 0.3%                              ______________________________________                                        1.  Normal eye                                                                              5       5     5     5     4     0                               2.  Normal eye                                                                              3.5     3.5   4.0   3.0   3.0   0                               3.  Normal eye                                                                              5       5     5     4.5   4.5   0                               4.  Corneal   --      --    --    --    4     --                                  Abrasion                                                                  5.  Keratitis 5       5     4.5   4.0   3.0   0                               6.  Corneal                                                                       Erosions                                                                      Right     4       5     4.5   4.5   5     0                                   Left      6       5     5.5   5.0   4.5   0                               ______________________________________                                    

When an anesthetic concentration (0.5% and above) of the anesthetic wasadministered to the eye, anesthesia of the cornea occurred, evidenced bythe complete loss of touch sensation. On the other hand, when ultralowsubanaesthetic concentrations (0.05% and below) of local anesthetic wereapplied to the cornea, analgesia was achieved without loss of cornealtouch sensation, that is, without inducing corneal anesthesia.Subanaesthetic concentrations of the local anesthetics produced ananalgesic effect when applied topically to the cornea.

In the same manner the anesthetics are formulated as gel, cream,suspension, ointment or in a sustained release vehicle.

EXAMPLE 5 Microsystem Delivery of the Topical Analgesic Preparation

This example describes an alternative preparation utilizing microsystemdelivery of the topical ophthalmic analgesic preparations. Themicrosystem utilizes either microdrop or microdose delivery and thenatural propensity of the eye to tear and in this way to dilute thehigher concentration of the anesthetic into the analgesic concentration.

The subanaesthetic concentrations used in this invention are determinedempirically, using drop volumes of approximately 30 μl. Since the volumeof the normal tear film is approximately 7 μl, some dilution of any dropoccurs when the drop is applied to the eye surface. Reflex tearinginduced by micro drop application increases this dilution effect.

When smaller drop volumes are used, in microdrops from about 1 to about10 μl, then surface dilution becomes a significant factor, and higherconcentrations of anesthetic are used to achieve analgesia withoutanesthesia or toxicity.

For this study, 1.0 μl of 1.0% of the topical anesthetic are applied tothe eye surface and the dilution is observed. A rapid dilution, tosubanesthetic concentration, occurs considering tear film volume andreflex tearing. Thus, in this case, the resulting drug concentration onthe eye surface is such that it provides analgesia but is notanesthetic.

This alternative method for achieving non-anesthetic and nontoxicconcentrations on the eye surface uses significantly smaller volumes ofhigher concentrations (>0.05%) of anesthetic solution.

EXAMPLE 6 Determination of Subanaesthetic Properties of Multiple Dosesof Dilute Topical Proparacaine

This example describes a study performed to determine, in adouble-masked fashion, if multiple doses of 0.05% topical proparacaineare subanaesthetic.

For this study, informed consent was obtained from ten healthyvolunteers with no history of neuropathy, diabetes, eye surgery, orrecent contact lens wear. Baseline corneal sensation was measured withthe Luneau esthesiometer. One drop of 0.05% proparacaine was placed inone eye and one drop of placebo was placed in the opposite eye in adouble-masked fashion. Drop application was repeated every 15 minutesfor two hours. Corneal sensation was measured one minute after each dropapplication.

The results are shown in FIG. 1. Multiple doses of 0.05% topicalproparacaine have subanaesthetic effect.

EXAMPLE 7 Gel and Ointment Compositions

This example provides listing of components present in gel or ointmentformulations.

Gel composition of the invention contains:

Proparacaine≦0.05%

Carbomer 940μ0.2%

Cetrimide

Disodium Acetate

Sorbitol

Sodium hydroxide to adjust pH.

Proparacaine may be substituted with any other topical anesthetic.Cetrimide may be substituted with other quarternary ammonium salt.

Ointment composition of the invention contains:

Proparacaine≦0.05%

White petrolatum

Light mineral oil

Purified water

Sodium Chloride

Proparacaine may be substituted with any other anesthetic.

What is claimed is:
 1. A topical ophthalmic analgesic preparationconsisting essentially of a subanaesthetic concentration of localanesthetic selected from the group consisting of proparacaine,tetracaine, lidocaine, benoxinate and bupivacaine, said preparationfurther containing pharmaceutically acceptable excipients, additives orpreservatives.
 2. The preparation of claim 1 formulated as an ointment,cream, suspension, solution, gel or a sustained release vehicle whereinthe subanaesthetic concentration is from about 0.001% to about 0.05%. 3.The preparation of claim 2 formulated as the ointment.
 4. Thepreparation of claim 2 formulated as the cream.
 5. The preparation ofclaim 2 formulated as the gel.
 6. The preparation of claim 2 formulatedas the sustained release vehicle.
 7. The preparation of claim 2 whereinthe anesthetic is proparacaine.
 8. The preparation of claim 2 whereinthe anesthetic is lidocaine.
 9. The preparation of claim 2 wherein theanesthetic is tetracaine.
 10. The preparation of claim 2 wherein theanesthetic is benoxinate.
 11. The preparation of claim 2 wherein theanesthetic is bupivacaine.
 12. A topical ophthalmic analgesicmicrosystem preparation for administration of local anesthetic selectedfrom the group consisting of proparacaine, tetracaine, lidocaine,benoxinate and bupivacaine said preparation optionally containingpharmaceutically acceptable excipients, additives or preservatives saidpreparation consisting essentially of from about 0.001% to about 1.0% ofsaid anesthetic diluted in about 1 to about 10 μl and administered inthis concentrated dosage.
 13. The preparation of claim 12 formulated asan ointment.
 14. The preparation of claim 12 formulated as a solution.15. The preparation of claim 12 formulated as a gel.
 16. The preparationof claim 12 formulated as a sustained release vehicle.
 17. Thepreparation of claim 12 wherein the anesthetic is proparacaine.
 18. Thepreparation of claim 12 wherein the anesthetic is lidocaine.
 19. Thepreparation of claim 12 wherein the anesthetic is tetracaine.
 20. Thepreparation of claim 12 wherein the anesthetic is benoxinate.
 21. Thepreparation of claim 12 wherein the anesthetic is bupivacaine.